Chemical reactions up close

Understanding the microscopic rearrangements of matter that occur during chemical reactions is of great importance for catalytic mechanisms and may lead to greater efficiencies in industrially relevant processes (1, 2). However, traditional chemical structure characterization methods are typically limited to ensemble techniques where different molecular structures, if present, are convolved in each measurement (3). This limitation complicates the determination of final chemical products, and often it renders such identification impossible for products present only in small amounts. Single-molecule characterization techniques such as scanning tunneling microscopy (STM) (4, 5) potentially provide a means for surpassing these limitations. Structural identification using STM, however, is limited by the microscopic contrast arising from the electronic local density of states (LDOS), which is not always easily related to chemical structure. Another important subnanometer-resolved technique is transmission electron microscopy (TEM). Here, however, the high-energy electron beam is often too destructive for organic molecule imaging. Recent advances in tuning fork–based noncontact atomic force microscopy (nc-AFM) provide a method capable of nondestructive subnanometer spatial resolution (6–10). Single-molecule images obtained with this technique are reminiscent of wire-frame chemical structures and even allow differences in chemical bond order to be identified (10). Here we show that it is possible to resolve with nc-AFM the intramolecular structural changes and bond rearrangements associated with complex surface-supported cyclization cascades, thereby revealing the microscopic processes involved in chemical reaction pathways.

Intramolecular structural characterization was performed on the products of a thermally induced enediyne cyclization of 1,2-bis((2-ethynylphenyl)ethynyl)benzene (1). Enediynes exhibit a variety of radical cyclization processes known to compete with traditional Bergman cyclizations (11, 12), thus often rendering numerous products with complex structures that are difficult to characterize using ensemble techniques (13). To directly image these products with subnanometer spatial resolution, we thermally activated the cyclization reaction on an atomically clean metallic surface under ultrahigh vacuum (UHV). We used STM and nc-AFM to probe both the reactant and final products at the single-molecule level. Our images reveal how the thermally induced complex bond rearrangement of 1 resulted in a variety of unexpected products, from which we have obtained a detailed mechanistic picture—corroborated by ab initio density functional theory (DFT) calculations—of the cyclization processes. 

We synthesized 1,2-bis((2-ethynylphenyl)ethynyl)benzene (1) through iterative Sonogashira cross-coupling reactions (scheme S1) (14). We deposited 1 from a Knudsen cell onto a Ag(100) surface held at room temperature under UHV. Molecule-decorated samples were transferred to a cryogenic imaging stage (T ≤ 7 K) before and after undergoing a thermal annealing step. Cryogenic imaging was performed both in a home-built T = 7 K scanning tunneling microscope and in a qPlus-equipped (15, 16) commercial Omicron LT-STM/AFM at T = 4 K. nc-AFM images were recorded by measuring the frequency shift of the qPlus resonator while scanning over the sample surface in constant-height mode. For nc-AFM measurements, the apex of the tip was first functionalized with a single CO molecule (6). To assess the reaction pathway energetics, we performed ab initio DFT calculations within the local density approximation (17) using the GPAW (Grid-based Projector Augmented Wavefunction) code (18, 19).

Figure 1A shows a representative STM image of 1 on Ag(100) before undergoing thermal annealing. The adsorbed molecules each exhibited three maxima in their LDOS at positions suggestive of the phenyl rings in 1(Fig. 1A). Annealing the molecule-decorated Ag surface up to 80°C left the structure of the molecules unchanged. Annealing the sample at T ≤ 90°C, however, induced a chemical transformation of 1 into distinctively different molecular products (some molecular desorption was observed). Figure 1B shows an STM image of the surface after annealing at 145°C for 1 min. Two of the reaction products can be seen in this image, labeled as 2and 3. The structures of the products are unambiguously distinguishable from one another and from the starting material 1, as shown in the close-up STM images of the most common products 2, 3, and 4 in Fig. 2, B to D. The observed product ratios are 2:3:4 = (51 ± 7%):(28 ± 5%):(7 ± 3%), with the remaining products comprising other minority monomers as well as fused oligomers (fig. S2) (14).

Detailed subnanometer-resolved structure and bond conformations of the molecular reactant 1 and products (2,3, and 4) were obtained by performing nc-AFM measurements of the molecule-decorated sample both before and after annealing at T ≥ 90°C. Figure 2E shows a nc-AFM image of 1 before annealing. In contrast to the STM image (Fig. 2A) of 1, which reflects the diffuse electronic LDOS of the molecule, the AFM image reveals the highly spatially resolved internal bond structure. A dark halo observed along the periphery of the molecule is associated with long-range electrostatic and van der Waals interactions (6, 20). The detailed intramolecular contrast arises from short-ranged Pauli repulsion, which is maximized in the regions of highest electron density (20). These regions include the atomic positions and the covalent bonds. Even subtle differences in the electron density attributed to specific bond orders can be distinguished (10), as evidenced by the enhanced contrast at the positions of the triple bonds within 1. This effect is to be distinguished from the enhanced contrast observed along the periphery of the molecule, where spurious effects (e.g., because of a smaller van der Waals background, enhanced electron density at the boundaries of the delocalized π-electron system, and molecular deviations from planarity) generally influence the contrast (10, 20).

Figure 2, F to H, shows subnanometer-resolved nc-AFM images of reaction products 2, 3, and 4 that were observed after annealing the sample at T > 90°C. The structure of these products remained unaltered even after further annealing to temperatures within the probed range from 90° to 150°C (150°C was the maximum annealing temperature explored in this study). The nc-AFM images reveal structural patterns of annulated six-, five-, and four-membered rings. The inferred molecular structures are shown in Fig. 2, J to L. Internal bond lengths measured by nc-AFM have previously been shown to correlate with Pauling bond order (10), but with deviations occurring near a molecule’s periphery, as described above. As a result, we could extract clear bonding geometries for the products (Fig. 2, J to L), but not their detailed bond order. The subtle radial streaking extending from the peripheral carbon atoms suggests that the valences of the carbon atoms are terminated by hydrogen (20). This is in agreement with molecular mass conservation for all proposed product structures and indicates that the chemical reactions leading to products 2, 3, and 4 are exclusively isomerization processes (21).

Our ability to directly visualize the bond geometry of the reaction products (Fig. 2, F to H) provides insight into the detailed thermal reaction mechanisms that convert 1 into the products. We limit our discussion to the reaction pathways leading from 1 to the two most abundant products, 2 and 3. The reactivity of oligo-1,2-diethynylbenzene 1 can be rationalized by treating the 1,2-diethynylbenzene subunits as independent but overlapping enediyne systems that are either substituted by two phenyl rings for the central enediyne, or by one phenyl ring and one hydrogen atom in the terminal segments. This treatment suggests three potential cyclizations along the reaction pathway (resulting in six-, five-, or four-membered rings) (22), in addition to other possible isomerization processes such as [1,2]-radical shifts or bond rotations that have been observed in related systems (23). Combinations of these processes leading to the products in a minimal number of steps were explored and analyzed using DFT calculations (14).

We started by calculating the total energy of a single adsorbed molecule of the reactant 1 on a Ag(100) surface. Activation barriers and the energy of metastable intermediates were calculated (including molecule-surface interactions) for a variety of isomeric structures along the reaction pathway leading toward the products 2 and 3. Our observations that the structure of reactants on Ag(100) remains unchanged for T < 90°C and that no reaction intermediates can be detected among the products indicate that the initial enediyne cyclization is associated with a notable activation barrier that represents the rate-determining step in the reaction. In agreement with experiments, DFT calculations predict an initial high barrier for the first cyclization reactions, followed by a series of lower barriers associated with subsequent bond rotations and hydrogen shifts.

Figure 3A shows the reaction pathway determined for the transformation of 1 into product 2. The rate-determining activation barrier is associated with a C¹–C⁶ Bergman cyclization of a terminal enediyne coupled with a C¹–C⁵ cyclization of the internal enediyne segment to give the intermediate diradical Int1 in an overall exothermic process (–60.8 kcal mol^–1). Rotation of the third enediyne subunit around a double bond, followed by the C¹–C⁵ cyclization of the fulvene radical with the remaining triple bond, leads to Int2. The rotation around the exocyclic double bond is hindered by the Ag surface and requires the breaking of the bond between the unsaturated valence on the sp² carbon atom and the Ag. Yet the activation barrier associated with this process does not exceed the energy of the starting material used as a reference. The formation of three new carbon-carbon bonds and the extended aromatic conjugation stabilize Int2 by –123.9 kcal mol^–1 relative to 1. Finally, a sequence of radical [1,2]- and [1,3]-hydrogen shifts followed by a C¹–C⁶ cyclization leads from Int2 directly to the dibenzofulvalene 2. Our calculations indicate that the substantial activation barriers generally associated with radical hydrogen shifts in the gas phase (50 to 60 kcal mol–1) (24, 25) are lowered through the stabilizing effect of the Ag atoms on the surface, and thus they do not represent a rate-limiting process (Fig. 3A).

The reaction sequence toward 3 is illustrated in Fig. 3B. The rate-determining first step involves two C¹–C⁵cyclizations of the sterically less hindered terminal enediynes to yield benzofulvene diradicals. The radicals localized on the exocyclic double bonds subsequently recombine in a formal C¹–C⁴ cyclization to yield the four-membered ring in the transient intermediate tInt1. This process involves the formation of three new carbon-carbon bonds, yet it lacks the aromatic stabilization associated with the formation of the naphthyl fragment inInt2 and is consequently less exothermic (–60.7 kcal mol^–1). A sequence of bond rotations transforms tInt1 viaInt3 into tInt2. Alignment of the unsaturated carbon valences in diradical tInt1 with underlying Ag atoms maximizes the interaction with the substrate and induces a highly nonplanar arrangement, thereby making subsequent rotations essentially barrierless. [1,2]-Hydrogen shifts and a formal C¹–C⁶ cyclization yield the biphenylene 3.

Both reaction pathways toward 2 and 3 involve C¹–C⁵ enediyne cyclizations. These are generally energetically less favorable relative to the preferred C1–C6 Bergman cyclizations (22), but factors such as the steric congestion induced by substituents on the alkynes (12, 22), the presence of metal catalysts (26), or single-electron reductions of enediynes (27, 28) have been shown to sway the balance toward C¹–C⁵ cyclizations yielding benzofulvene diradicals. All three of these factors apply to the present case of the thermally induced cyclization of 1 on Ag(100) [e.g., bulky phenyl substituent on C¹ and C⁶, a metallic substrate, and a charge transfer of 0.5 electrons from the substrate to 1 (14)], thus facilitating the C¹–C⁵ cyclizations. The precise order of the low-energy processes (such as the Int3-tInt2 rotation and the tInt2-3 [1,2]-hydrogen shifts) following the rate-limiting initial cyclizations cannot be strictly determined experimentally. However, the sequence does not change the overall reaction kinetics and thermodynamics discussed above. Our bond-resolved single-molecule imaging thus allows us to extract an exhaustive picture and unparalleled insight into the chemistry involved in complex enediyne cyclization cascades on Ag(100) surfaces. This detailed mechanistic understanding in turn guides the design of precursors for the rational synthesis of functional surface-supported molecular architectures.

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35. Acknowledgments: Supported by the Office of Naval Research BRC Program (molecular synthesis, characterization, and STM imaging); the Helios Solar Energy Research Center supported by the Office of Science, Office of Basic Energy Sciences, U.S. Department of Energy under contract DE-AC02-05CH11231 (STM and nc-AFM instrumentation development, AFM operation); NSF grant DMR-1206512 (image analysis); and European Research Council advanced grant DYNamo ERC-2010-AdG-267374 (ab initio calculations). Computing time was provided by the Barcelona Supercomputing Center “Red Española de Supercomputacion.” D.G.d.O. acknowledges fellowship support by the European Union under FP7-PEOPLE-2010-IOF-271909, A.R. by Austrian Science Fund (FWF) grant J3026-N16, and D.J.M. by the Spanish “Juan de la Cierva” program (JCI-2010-08156). The data presented in the manuscript are tabulated in the main paper and in the supplementary materials. The authors declare no conflicts of interest.